Nrf2 suppresses allergic lung inflammation by attenuating the type 2 innate lymphoid cell response

Ryuichi Nagashima, Hitomi Kosai, Masahiro Masuo, Keiko Izumiyama, Taketo Noshikawaji, Motoko Morimoto, Satoru Kumaki, Yasunari Miyazaki, Hozumi Motohashi, Masayuki Yamamoto, Nobuyuki Tanaka

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


The Keap1–Nrf2 system plays a pivotal role in the oxidative stress response by inducing a number of cytoprotective genes. Under stress, damaged epithelial cells release cytokines that activate type 2 innate lymphoid cells (ILC2s), which mediate the allergic immune response. In this article, we investigated the role of the Keap1–Nrf2 pathway in ILC2 homeostasis and allergic inflammation using Nrf2 knockout mice. ILC2s from Nrf2-deficient mice showed a transient, upregulated IL-33 response and underwent hyperproliferation in response to a combined stimulation of IL-33 with IL-2, IL-7, or TSLP. This enhanced proliferation was correlated with an increased activation of downstream signals, including JAK1, Akt, and Erk1/2. In contrast, activating Nrf2 with a chemical inducer (CDDO-Im) decreased the viability of the wild-type but not of the Nrf2-deficient ILC2s. This effect on viability resembled that exerted by the corticosteroid dexamethasone; however, unlike the latter, the Nrf2-dependent cell death was mediated by neither caspase 3–dependent apoptosis nor necroptosis. Using a mouse intratracheal IL-33 administration allergy model, we found that the activation of Nrf2 by CDDO-Im in vivo decreased the number of pulmonary ILC2s and eosinophils. These findings indicated that Nrf2 is an important regulator of the allergic response by determining the survival and death of ILC2s, and these findings suggest that Nrf2 activation is a potential therapeutic strategy for steroid-resistant allergy alleviation.

Original languageEnglish
Pages (from-to)1331-1339
Number of pages9
JournalJournal of Immunology
Issue number5
Publication statusPublished - 2019 Mar 1


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